Molecular Cancer Research最新文献

{"title":"StarD5 Regulates Cholesterol Homeostasis to Promote Colorectal Cancer Progression and the Cancer Stem Cell Phenotype.","authors":"Chetna Sharon, Daniel Rodriguez-Agudo, Rio S Boothello, Shoja M Haneefa, William M Pandak, Gregorio Gil, Bhaumik B Patel","doi":"10.1158/1541-7786.MCR-23-1084","DOIUrl":"10.1158/1541-7786.MCR-23-1084","url":null,"abstract":"<p><p>An aberration in cellular, especially plasma membrane (PM), cholesterol level is arguably the most critical targetable hallmark of colorectal cancer and colorectal cancer stem cell (CRCSC) phenotypes. We recently identified Star-related lipid transfer protein 5 (StarD5) as an intracellular cholesterol transport protein that regulates PM cholesterol levels. In this study, we show that StarD5 protein levels are significantly elevated in most human colorectal cancer tissues compared with adjacent normal mucosa, with a preferential increase in the epithelial compartment. Additionally, allograft growth in StarD5 knockout mice was largely unaffected. StarD5 levels were particularly elevated in CRCSCs compared with non-CRCSCs in several colon cancer cell lines and primary human colorectal cancer samples. Genetic knockdown of StarD5 (shRNA; KD) inhibited the CRCSC phenotype in vitro-growth and self-renewal (1°→3° spheroid formation), CRCSC maker levels, and sensitivity to 5-fluorouracil. Also, StarD5-depleted HT-29 cells showed a robust (40-fold) reduction in tumor formation (CRCSC characteristics) in vivo and CRCSC phenotype ex vivo, including CRCSC marker expression and spheroid formation (1°→3°). StarD5 inhibition also caused a significant increase in apoptosis induction. Mechanistically, PM cholesterol levels were significantly higher in CRCSCs than in non-CRCSCs, and StarD5 depletion decreased accessible PM cholesterol, particularly in specialized lipid raft domains. Finally, cholesterol depletion in the PM is critical for StarD5 KD's inhibition of the CRCSC phenotype as supplementation with low-density lipoprotein caused a significant reversal of the StarD5 KD effects on PM/raft cholesterol levels and the CRCSC phenotype.</p><p><strong>Implications: </strong>Given StarD5's critical role in regulation of CRCSCs, translational research targeting StarD5 will lead to improved outcomes in patients with colorectal cancer.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"649-659"},"PeriodicalIF":5.8,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13234776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147639159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNMT3B drives neuroendocrine lineage plasticity and aggressive progression in prostate cancer.","authors":"Yunsol Jo, Hyeryeon Jung, Ziqin Wang, David Lee, Andrew Tran, Brandon Tsai, Ting Zhao, Furong Huang, Issac Jung, Changhyeon Hong, Erin Lim, Sanjeevram Dhandapani, Yinsheng Wang, Yuzhuo Wang, Jiaoti Huang, Jung Wook Park","doi":"10.1158/1541-7786.MCR-25-1300","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-1300","url":null,"abstract":"<p><p>Neuroendocrine prostate cancer (NEPC) is an aggressive and therapy-resistant subtype of advanced prostate cancer characterized by poor prognosis and limited treatment options. Enzalutamide, an androgen receptor (AR) pathway inhibitor, is a standard second-line therapy for prostate adenocarcinoma (PrAd). However, enzalutamide resistance (EnzR) promotes not only neuroendocrine differentiation (NED) but also the induction of stemness-associated programs in PrAd cells. We identified the de novo DNA methyltransferase DNMT3B as a stemness-related gene upregulated in EnzR-PrAd cells and found that its expression is further significantly elevated in NEPC compared with PrAd. Our studies reveal that DNMT3B is a critical driver of NEPC development by coordinating the regulation of neuroendocrine and stemness transcriptional networks. Genetic inhibition of DNMT3B suppresses NEPC cell proliferation by impairing cell-cycle progression and triggering apoptosis both in vitro and in vivo. DNMT3B loss altered NED-associated, stemness, and epithelial-associated genes. We further uncover a reciprocal regulatory relationship between DNMT3B and the neuroendocrine transcriptional repressor REST. Using a human prostate cell transformation model that recapitulates NEPC evolution, we demonstrate that DNMT3B is required for both the initiation and maintenance of the NEPC phenotype. Finally, pharmacologic inhibition of DNMT3B with the selective inhibitor Nanaomycin A reduces NEPC tumor growth and suppresses NED and stemness marker expression without apparent acute toxicity in vivo. Implications: DNMT3B drives therapy-induced lineage plasticity in prostate cancer, and its inhibition suppresses NEPC growth and differentiation, highlighting it as a promising therapeutic target for treatment-resistant disease.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3beta-HSD1-mediated steroid back-conversion maintains androgen signaling in prostate cancer.","authors":"Masoud Bitaraf, Mohammad Alyamani, Nikou Fotouhi, Jinyuan Shi, Ziqi Zhu, Yoon-Mi Chung, Jennifer Freedman, Daniel J George, Nima Sharifi","doi":"10.1158/1541-7786.MCR-26-0243","DOIUrl":"10.1158/1541-7786.MCR-26-0243","url":null,"abstract":"<p><p>Dihydrotestosterone (DHT), the principal driver of prostate cancer, is inactivated via reduction of its 3-keto group to a 3β-hydroxyl (3β-OH). 3β-Hydroxysteroid dehydrogenase type 1 (3β-HSD1), encoded by HSD3B1, catalyzes 3β-OH oxidation and is stabilized by an adrenal-permissive germline variant, thereby enhancing androgen biosynthesis. Here, we tested whether 3β-HSD1 maintains androgen receptor (AR) signaling by back-converting the inactive metabolite 3β-androstanediol (3β-diol) to DHT, and whether it similarly oxidizes the abiraterone metabolite 3β-OH-5α-abiraterone (3β-OH-5α-Abi) to 3-keto-5α-Abi, a weak AR agonist. Using HSD3B1-overexpression and knockout in vitro models, we quantified steroid interconversion by mass spectrometry and AR-responsive gene expression by qPCR and RNA sequencing following 3β-diol exposure. HSD3B1 overexpression efficiently enabled the conversion of 3β-diol to DHT and 3β-OH-5α-Abi to 3-keto-5α-Abi. In C4-2 prostate cancer cells, 3β-diol-derived DHT regeneration and subsequent AR gene induction were blocked by the 3β-HSD1 inhibitor trilostane or abolished by HSD3B1 knockout. Clinically, in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone, apalutamide, and prednisone in the PANTHER trial, men harboring the adrenal-permissive HSD3B1 genotype showed significantly greater serum depletion of 3β-OH-5α-Abi. These findings demonstrate that 3β-HSD1-mediated steroid back-conversion can maintain intratumoral androgens, providing further mechanistic insight into the poor outcomes associated with the adrenal-permissive HSD3B1 genotype and highlighting 3β-HSD1 as a critical therapeutic target in prostate cancer. Implications: 3β-HSD1-mediated back-conversion of inactivated androgens (3β-diol→DHT) and abiraterone metabolites (3β-OH-5α-Abi→3-keto-5α-Abi) regenerates AR-active ligands, supporting sustained AR signaling and motivating 3β-HSD1 targeting and HSD3B1 genotype-informed treatment strategies in CRPC.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13458341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148605650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The PON1-NDUFA4 axis maintains mitochondrial respiratory fitness and drives lenvatinib tolerance in hepatocellular carcinoma.","authors":"Shi-Lin Lin, Yue Wang, Yi-Min Zheng, Ai-Wu Ke, A-Ying Ma, Chao Gao","doi":"10.1158/1541-7786.MCR-26-0121","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-26-0121","url":null,"abstract":"<p><p>Metabolic plasticity driven by mitochondrial oxidative phosphorylation (OXPHOS) is increasingly recognized as a key determinant of therapeutic tolerance in hepatocellular carcinoma (HCC), but the upstream regulators that preserve electron transport chain stability during treatment remain poorly defined. In this study, we identified paraoxonase-1 (PON1) as a clinically relevant regulator of mitochondrial metabolism and lenvatinib response in HCC. PON1 was markedly upregulated in HCC and independently associated with poor overall and recurrence-free survival. Functionally, PON1 promoted tumor growth and conferred robust tolerance to lenvatinib. Mechanistically, PON1 directly interacted with and stabilized NDUFA4, a key component required for complex IV assembly, thereby maintaining mitochondrial membrane potential, complex IV integrity, and OXPHOS-dependent adenosine triphosphate production while limiting reactive oxygen species accumulation. Genetic silencing of PON1 or NDUFA4 impaired mitochondrial respiration, increased oxidative stress, and restored lenvatinib sensitivity in HCC cells and xenograft models. Structure-guided virtual screening identified the Food and Drug Administration-approved CFTR corrector lumacaftor as a potent modulator of PON1 that disrupted the PON1-NDUFA4 interaction and enhanced the antitumor efficacy of lenvatinib in vivo. These findings identify the PON1-NDUFA4 axis as a previously unrecognized metabolic vulnerability that sustains mitochondrial respiratory fitness and lenvatinib resistance in HCC. Targeting mitochondrial protein-stabilizing mechanisms such as PON1-NDUFA4 may offer a broadly applicable strategy for overcoming therapy resistance in liver cancer and other aggressive malignancies. Implications: These findings establish mitochondrial protein stabilization as an actionable therapeutic vulnerability and provide a rationale for combination strategies to overcome targeted therapy resistance in HCC.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148605677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"COL1A1-Mediated Bmp1/Tgf-β Signaling Augments EMT and M2 Macrophage Polarization in Oral Squamous Cell Carcinoma.","authors":"Xing Liu, Yalun Li, Lanlan Gao, Rihui Lu, Yongjin Fang, Xiao Yang","doi":"10.1158/1541-7786.MCR-25-1164","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-1164","url":null,"abstract":"<p><p>Oral squamous cell carcinoma (OSCC) is a lethal malignancy characterized by frequent metastasis. Utilizing a 4-NQO-induced murine model and single-cell RNA sequencing, we identified a distinct Collagen Type I Alpha 1 Chain (Col1a1+) epithelial subpopulation that is significantly expanded in OSCC, exhibits the highest epithelial-mesenchymal transition (EMT) signature, and correlates with poor patient survival. Functional studies demonstrated that Col1a1 knockdown in OSCC cell lines (HSC3, SCC25) attenuated TGF-β-induced EMT, impaired migration and invasion in vitro, and reduced tumor burden in a conditional knockout mouse model. Transcriptomic profiling following Col1a1 silencing revealed the suppression of TGF-β signaling and ECM-receptor interaction pathways. We further identified BMP1 as a key downstream effector, demonstrating a direct physical interaction between COL1A1 and BMP1, and showed that COL1A1 potentiates BMP1's proteolytic activity. Rescue experiments confirmed that BMP1 is essential for COL1A1-driven tumor growth, metastasis, and TGF-β pathway activation in vivo. Furthermore, we uncovered an immunomodulatory role for the COL1A1-BMP1 axis, whereby it promotes M2 macrophage polarization via TGF-β secretion to foster an immunosuppressive tumor microenvironment. This effect was reversible using either BMP1 knockdown or TGF-β neutralization. In conclusion, our study establishes a novel COL1A1-BMP1-TGF-β signaling cascade that drives OSCC progression by autonomously enhancing tumor cell malignancy and non-autonomously reprogramming the immune landscape, nominating this axis as a promising therapeutic target. Implications: These findings identify a novel COL1A1-BMP1 axis driving both OSCC malignancy and immunosuppression, offering potential diagnostic markers and therapeutic targets for the clinic.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ETS1-Driven Transcriptional Activation of USP43 Promotes Lenvatinib Resistance in Hepatocellular Carcinoma through MYH9 Stabilization and AKT/BAD Signaling.","authors":"Wen Chen, Zhenheng Wu, Wei Pan, Lupeng Wu, Shenzhe Lin, Xiahenazi Abudukeremu, Canze Wu, Xinyue Yang, Feifei She, Yanling Chen","doi":"10.1158/1541-7786.MCR-25-0931","DOIUrl":"10.1158/1541-7786.MCR-25-0931","url":null,"abstract":"<p><p>Lenvatinib, a first-line targeted therapy for advanced hepatocellular carcinoma (HCC), exhibits significant clinical efficacy. At present, there remains a scarcity of effective treatment options for patients experiencing lenvatinib resistance. This study aims to identify and validate molecular markers capable of predicting the therapeutic response of patients with HCC to lenvatinib treatment. We successfully established a lenvatinib-resistant HCC cell line (Huh7/LR) through progressive exposure of parental Huh7 cells to lenvatinib. Through RNA sequencing analysis, ubiquitin-specific protease 43 (USP43) was ultimately pinpointed as a potential key molecule related to lenvatinib resistance. The expression of USP43 is notably elevated in lenvatinib-resistant HCC cells and tissues, correlating with a poor prognosis for HCC. USP43 promotes the proliferation of HCC cells, suppresses apoptosis, and enhances resistance to lenvatinib. Mechanistically, E26 transformation-specific 1 (ETS1) transcriptionally upregulates USP43. USP43 then binds to nonmuscle myosin heavy chain 9 (MYH9) and removes its K48-linked polyubiquitination. This stabilizes the MYH9 protein by preventing its degradation through the ubiquitin-proteasome pathway and further activates the AKT/BAD signaling axis, ultimately suppressing apoptosis and conferring lenvatinib resistance.</p><p><strong>Implications: </strong>Targeting the ETS1/USP43/MYH9 axis presents a promising therapeutic strategy to overcome lenvatinib resistance in HCC.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"539-554"},"PeriodicalIF":5.8,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147468934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gastric Epithelium from BRCA1 and BRCA2 Carriers Harbors Increased Double-Stranded DNA Damage and Enhanced Growth Potential.","authors":"Kole H Buckley, Michaela E Dungan, Kevin Dinh, Gregory M Kelly, Ryan Hausler, Kate E Bennett, Daniel G Clay, Julia E Youngman, Ariana D Majer, Keely A Beyries, Blake A Niccum, Sydney M Shaffer, Tatiana A Karakasheva, Kathryn E Hamilton, Michael L Kochman, Gregory G Ginsberg, Nuzhat Ahmad, Kara N Maxwell, Bryson W Katona","doi":"10.1158/1541-7786.MCR-25-0970","DOIUrl":"10.1158/1541-7786.MCR-25-0970","url":null,"abstract":"<p><p>An accumulating body of evidence suggests that carriers of a pathogenic germline variant (PGV) in BRCA1 or BRCA2 have an increased gastric cancer risk. BRCA1 and BRCA2 are tumor suppressor genes involved in promoting homologous recombination to repair double-stranded DNA breaks. The aim of this investigation was to identify differences within the gastric epithelium and in patient-derived gastric organoids (PDGO) between BRCA1 and BRCA2 carriers and noncarriers to determine if evidence of early gastric carcinogenesis exists among these carriers. First, using gastric epithelial biopsies, BRCA2 carriers were found to harbor higher expression of the proliferative marker Ki-67 within the antral gastric epithelium, and strikingly, biopsies from both BRCA1 and BRCA2 carriers displayed a marked increase in double-stranded DNA damage. These results were further explored using PDGOs, in which a growth advantage was observed for both BRCA1 and BRCA2 PDGOs compared with noncarrier PDGOs. Furthermore, both BRCA1 and BRCA2 PDGOs displayed a more pronounced enhancement of Ki-67 expression as well as increased double-stranded DNA damage compared with noncarrier PDGOs. Importantly, none of the PDGOs showed signs of BRCA1 or BRCA2 loss of heterozygosity, potentially indicating a haploinsufficient phenotype. Taken together, these novel findings suggest that haploinsufficiency in BRCA1 and BRCA2 carriers may lead to DNA damage in the gastric epithelium, which may serve as an early event contributing to gastric cancer development.</p><p><strong>Implications: </strong>The elevated risk of gastric cancer for BRCA1 and BRCA2 PGV carriers may be due to haploinsufficiency, which warrants further investigation into mechanisms of BRCA1- and BRCA2-associated gastric cancer.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"589-600"},"PeriodicalIF":5.8,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147499736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of USP7 Destabilizes the Noncanonical PRC1.1 Complex and Induces Neuroblastoma Differentiation.","authors":"Emily A Cmarik, Abhishek Wahi, Sayali S Chandekar, Solomon K Otchere, Jennifer E Sturgis, Silvi Salhotra, Allen T Basanthakumar, Nehemiah X Boyd, Giulia DiGiovanni, He Zhu, Gabriela Alexe, Daniel A Schaefer, Xing Liu, Jarrod A Marto, Sara J Buhrlage, Kimberly Stegmaier, Nathaniel W Mabe","doi":"10.1158/1541-7786.MCR-25-1153","DOIUrl":"10.1158/1541-7786.MCR-25-1153","url":null,"abstract":"<p><p>Pediatric cancers are frequently driven by genomic alterations that result in impaired differentiation during development. To identify complex-level dependencies required for differentiation in neuroblastoma, a pediatric cancer of the developing peripheral nervous system, we curated a list of protein complexes using the CORUM database and mined the Dependency Map using gene set enrichment analysis. This analysis identified the noncanonical polycomb repressive complex 1.1 (PRC1.1) complex, which represses transcriptional activity through ubiquitination of histone 2A, lysine 119 (H2AK119Ub), as a selectively enriched dependency in neuroblastoma. Knockout of PRC1.1 subunits reduced neuroblastoma growth by inducing a neuronal differentiation program. Although no known direct inhibitors of PRC1.1 exist, codependency analysis identified that the deubiquitinase USP7 strongly correlated with PRC1.1 dependency. Treatment with XL177A, a small molecule inhibitor of USP7, significantly reduced neuroblastoma growth in both cellular and animal models. Integrated RNA and chromatin immunoprecipitation sequencing showed that both PRC1.1 knockout and USP7 inhibition resulted in highly correlated transcriptional alterations and reduced H2AK119Ub deposition on chromatin, suggesting that USP7 inhibition reduced neuroblastoma growth through a PRC1.1-dependent mechanism. Mechanistically, global proteomics and ubiquitinomics revealed that USP7 inhibition disrupted noncanonical PRC1 complex assembly, resulting in the destabilization of PRC1.1 and subsequent proteolysis. Our findings expand our understanding of the chromatin complexes required to maintain a dedifferentiated state in neuroblastoma and suggest the therapeutic potential for USP7 inhibitors in the treatment of this disease.</p><p><strong>Implications: </strong>Our study reveals the potential for utilizing USP7 inhibitors to target epigenetic repression of differentiation programs in neuroblastoma by reducing PRC1 activity.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"555-575"},"PeriodicalIF":5.8,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13082235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147487062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Personalized Therapeutic Approach for Liver Cancers Expressing the African-Centric P47S Variant of TP53.","authors":"Maya Foster, Kaitlyn Casey, Joel Cassel, Ying Ye, Jason Diaz, Kristy Shuda McGuire, Thibaut Barnoud, Maureen E Murphy","doi":"10.1158/1541-7786.MCR-25-1297","DOIUrl":"10.1158/1541-7786.MCR-25-1297","url":null,"abstract":"<p><p>The P47S missense germline variant of TP53 exists in approximately 2% of Americans of African descent and may account for the increased cancer risk and poorer response to therapy evident in African-descent populations. In this work, we sought to identify personalized therapeutic approaches for cancer containing the P47S variant, with a focus on the most common cancer evident in the P47S mouse, liver cancer. We identify the microtubule-targeting agents lexibulin, colchicine, and combretastatin A-4 as three compounds that bind to the colchicine-binding pocket of the α/β-tubulin dimer, and which show increased efficacy in a P47S liver cancer cell line compared with parental cells with wild-type p53. We find evidence for an unusual mechanism underlying this increased efficacy: Our data indicate that the P47S variant shows increased ability to bind to the peptidyl-prolyl isomerase PIN1; this leads to decreased PIN1-cyclin D1 complexes in P47S cells, along with increased cell-cycle arrest in response to lexibulin.</p><p><strong>Implications: </strong>These findings support the growing literature that particular mutant forms of TP53 may have specific therapeutic vulnerabilities that can be targetable; improved understanding of these unique vulnerabilities can lead to improved understanding of p53 function.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"618-629"},"PeriodicalIF":5.8,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13147292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147487002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interaction of NDRG1 and TGM2 Modulates DNA Replication and Repair.","authors":"Hanna M Doh, Nina Kozlova, Kayla A Cruz, Taru Muranen","doi":"10.1158/1541-7786.MCR-25-0743","DOIUrl":"10.1158/1541-7786.MCR-25-0743","url":null,"abstract":"<p><p>In tumor cells, DNA replication is constantly challenged by endogenous and exogenous sources, referred to as replication stress, and various pathways have evolved to mitigate this stress in cancer. We recently identified an extracellular matrix (ECM)-induced DNA repair pathway involving N-myc downstream regulated gene 1 (NDRG1). Matrix-induced signaling results in NDRG1-dependent protection from chemotherapy-induced replication stress. To uncover further mechanistic details of NDRG1-mediated effects on DNA replication, we identified transglutaminase 2 (TGM2) as a novel NDRG1-binding partner. TGM2 is an acyltransferase that catalyzes Ca(2+)-dependent protein modifications. This interaction was enriched upon chemotherapy-induced replication stress and also upon ECM-induced signaling. Our data show that TGM2 depletion significantly slows replication fork progression, and this phenotype is dependent on TGM2 catalytic activity and its nuclear localization. Our study further identifies a putative NDRG1-TGM2 binding site and shows that the physical interaction between NDRG1 and TGM2 is required for efficient DNA replication.</p><p><strong>Implications: </strong>This study reveals a previously unrecognized nuclear function for NDRG1 and TGM2 in regulating DNA replication fork stability and recovery, and uncovers a stress-responsive mechanism that supports replication homeostasis in cancer cells and advances our understanding of how extracellular signals are integrated with replication and repair pathways.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"601-617"},"PeriodicalIF":5.8,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13112271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}